Manufacture of substituted malonic acid esters



Patented Apr. 16, was

UNITED STATES.

PATENT OFFICE MANUFACTURE OF SUBSTITUTED MALONIG om ESTERS Thomas S. Carswell, Kirkwood, and Harry W.

Faust, St. Louis, Mo., assignors, by mesne assignments, to Monsanto Chemical Company, a corporation of Delaware No Drawing. Application March 14, 1932, SerialNo. 598,872

'1 Claims. (01. 260-106) This invention relates to the manufacture of alkyl and aralkyl derivatives of malonic acid esters, and it has particular application to the manufacture of mono and .di alliyl or aralkyl C-substituted derivatives of esters of malonic acid.

The mono and di-alkyl C-substituted derivatives of malonic acid ester are intermediates in the manufacture of barbituric acid derivatives. ,Heretofore, it has been the practice to manufacture the di-alkyl C-substituted malonic acid esters by reacting malonic acid ester with a mol. equivalent of sodium ethylate according to the following reaction:

and thereafter displace the sodium with an alkyl group by means of an alkyl halide according to the following reaction:

The resulting mono-alkyl derivative is then reacted with a second mol. equivalent of sodium ethylate and the combined sodium is then re- 7 placed with an alkyl group by means of its corresponding halide.

Although it has been proposed to proceed from one alkylation to the next without isolating the mono-alkyl product, in practice it is preferable because of the improved yields thereby made possible to isolate the intermediateproduct from r the impurities and by-products. Even then, however, the overall yield by the two-stage process seldom exceeds of theory.

. We have found that by reacting the alkyl halide with the malonic acid ester in the presence of an alkali-alcoholate, while avoiding a substantial excess of the alkali metal derivative of the malonic acid ester, one can proceed directly to the di-substituted derivative without isolating the intermediate products. The yields thus obtainable are materially greater than those otherwise obtainable and-the processing operations and costs are at the same time reduced.

The principal object of the present invention is to provide a method of effecting the alkyl or aralkyl substitution directly, and with improved yields as compared to those attainable by present day methods.

The invention likewise contemplates eliminatand while agitating the reaction mixture.

ing several steps of the process now commonly employed.

A further object of the invention is to provide. a process by which it is possible to reduce to a minimum the destructive effect of the alkali on the malonic acid ester which effect we have found contributes very greatly to the comparatively low yield of product. These together with other objects will be more apparent from the descriptionof .an embodiment of the process hereinafter set forth.

To manufacture the C-di-ethyl malonic acid ester, which may be represented structurally:

cohol is added slowly over a period of two hours 30 while. maintaining a temperature of 50-60 C. The sodium derivative thus produced reacts under the prevailing conditions with the ethylating agent. The sodium ethylate reagent is prepared 35 conveniently by dissolving approximately parts by weight of metallic sodium in 875 parts by weight of absolute ethyl alcohol. Subsequently, the temperature of the reaction mixture is raised to approximately C. and the reaction 40 is allowed to proceed for approximately two hours. At the end of this period, the mono-ethyl substitution is essentially complete.

To prepare the di-ethyl derivative, the temperature of the reaction mixture is again'adjusted to approximately 50-60 C. and a mol equivalentof ethyl chloride is introduced, after which a mol equivalent of sodium ethylate dissolved in ethyl alcohol is, introduced over a period of two hours as in the preceding stage. At the end of 5 the two hour period, the temperature is raised again to aproximately 90 C. and maintained for approximately two hours. A 90% yield of the diethylated malonic acid ester is obtained, which is separated and purified in the usual manner. 55

If one desires to prepare the ethyl butyl derivative in lieu of the di-ethyl derivative, butyl chloride is introduced at the end of the first stage in lieu of ethyl chloride. For this purpose, one may also substitute sodium butylate dissolved in butyl alcohol for the sodium ethylate reagent as well as remove'the ethyl alcohol introduced in the'first stage and substitute a butyl alcohol corresponding to the alkylating agent to be employed in the second stage.

The corresponding benzylated malonic acid ester is prepared by a method analogous to that described above. Similarly, one may prepare the ethyl benzyl derivative by substituting benzyl; chloride for the ethyl chloride'which is'employe'd'i in the second stage of the reaction.

It is to be noted that the temperatures specifi'r cally set forth may be varied. In general'jit is preferable to increase the temperature during the later stages of each alkylation. If desireclfliowever, the temperature may be increased gradually.

during the reaction cycle, although in general :we prefer to introduce all of the alcoholate before raising the temperature. It islikewiseto be noted that theforegoing examples provide for a two stage ethylation in the preparation of the C-diethyl malonic ester. This precise cycle'of operation is not essential,'but is rather a matter of con venience, since the mono ethyl product obtained after the first stage may be employed in the prep.-

Similarly, the concentration of the alcoholate in the alcohol solvent may be varied;

If desired, the alkylating agent may be introduced simultaneously with the alcoholate. Or, when the di-alkyl derivative'is desired, two mol equivalents of the alkylating agent-may be introduced at the outset. We havelikewiseobserved that one may reactthe malonic acid ester with,

a portion of the alcoholatepreliminary to the introduction of the alkylating agent. it is desirable to avoid the presence of a'substantial proportion of the alkali metal derivative of the malonic acid ester, such as prevailsunder the conditions of the present day processes wherein the mono-alkali metal derivative of malonic acid ester is-formed preliminary to the introduction of the'alkylating agent.

In lieu of'ethyl chloride, one may employ other alkylating agents, such as the bromide; di-ethyl sulfate, di-ethyl sulfite, etc. Other alkyl derivatives may be produced in an analogous manner'by appropriate substitution of the corresponding alkylating agents. Thus for example, methyl, propyl, butyl halides may be employed in the preparation of the corresponding derivative of the'malonic acid esteri' Similarly, an aralkylating agent, such as benzyl chloride or bromben'zyl' chloride, may" be employed whereby the 'corre spending aralkyl derivatives of the ester arepro- In general,

duced. Alcoholates other than the sodium ethyl ate which may be employed include: potassium ethylate, sodium methylate, sodium butylate, etc.

The term malonic acid ester is generally understood in the art to mean the di-ethyl ester of malonic'acid. However, as used herein it is not so limited, but is intended to cover other esters including for example diemethyl or di-butyl ester of malonic acid.

Fromthe foregoing description, it will be apparentthat we have provided a method for manufacturingmono and di-substituted malonic acid e'sterswhereby the intermediate steps now commonly}. employed a'reeliminated, with improvementjin yield of the, desired product. It will likewisebe a parent'that although one specific embodimenthas been set forth and certain modifications have been indicated, the invention is not so limited, but contemplates broadly the interaction of a malonic acid ester with an alkylating or aralkylatingagentfin. the presence of an alkali metal alcoholatewhilelavoidingthe presence of a substantialquantity of.unreacted alkali metal substituted malonic acid ester.

What ,we claim is;

1. The method which consists in causing a malonic acid esterto react witha material-selected from agroup-consistingof an alkylating agent andanaralkylating agent, while adding progressivelyduring the course of the reaction an alkali metal alcoholate.

2. The method which consists in causing the di ethyl ester of malonicacid to react with an, alkylating agent while adding progressivelyduring the course of. the reaction an alkali metal alcoholate.

3. The method as defined in claim 2 and further characterized in that the alcoholate is sodium, ethylate.

4. The method. which consists in, reacting the di-ethyl' ester'bfmalonic acidwith a mol equivalent of an ethylating agent while adding during the course of the reaction substantially one mol of sodium ethylate. and avoiding. the. presence of a substantial unreacted excess of the sodium ethylate 5. The method as defined in claim and further characterized in that the resulting reaction product is caused toreact with. a second mol equivalent of ethylating agent while adding during the course of the reaction a second mol equivalent of sodium-ethylate and avoiding. the presence of a substantial unreacted. excess of the sodium ethylate.

6.,.'I'he method which consists. in causing a malonic acid ester to. react with a material se lected from the group consisting. of an alkylating agent and an aralkylating agent, which method is characterized in that an alkali metal alcoholate isadd'ed progressively during the course of the reaction while avoiding the presence of a substantialrquantity of the alkali metal alcoholate in the reacting. mixture.

7. The method as defined in claim 6 and further characterizedin that the alkalimetal alcoholate reagent is dissolvedinthe corresponding alcohol;

THOMAS S. CARSWELL.

HARRY W. FAUST. 

